The human NLGN1, NLGN3 and NLGN4X genes have been identified as susceptibility loci for autism spectrum disorder (FBhh0000514). These genes encode neuroligins, which are ligands of neurexin; the neurexin/neuroligin complex is present at neural synapses and is required for efficient neurotransmission and in the formation of synaptic contacts. There are multiple neuroligin genes in both human and Drosophila; Dmel\Nlg2, Dmel\Nlg3 and Dmel\Nlg4 have been used to investigate the role of neuroligins in the development of autism spectrum disorder. Loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated for both Drosophila genes.
UAS constructs of the human Hsap\NLGN1 gene, including wild-type and a variant postulated to be associated with autism, have been introduced into flies and are available. A UAS construct of the human Hsap\NLGN3 gene carrying a variant postulated to be associated with autism has been introduced into flies and is available. See the 'Disease-Implicated Variants' table below. The human NLGN4X gene has been introduced into flies.
Amorphic mutations of Dmel\Nlg4 are homozygous lethal. RNAi-effected loss of function leads to reduced behavioral flexibility as shown by severe reversal-learning impairment; it is postulated that this phenotype results from the failure to properly activate Rac1-dependent forgetting. An amorphic mutation of Dmel\Nlg2 is viable and fertile, but exhibits behavioral, locomotor, and neurophysiology defects. Loss-of-function mutations of Dmel\Nlg3 result in locomotor defects; an amorphic genotype also results in sex-specific social distancing defects. Pan-neuronal overexpression of Nlg3 results in sex-specific social distancing defects and other behavioral phenotypes.
Experiments in flies include characterization of a mutation in Nlg2 analogous to an NLGN3 variant associated with autism in human; see the human disease report 'autism spectrum disorder, susceptibility to, X-linked 1' (FBhh0000521) and the 'Disease-Implicated Variants' table below.
[updated Mar. 2022 by FlyBase; FBrf0222196]
Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996, pubmed:8655659; Risch et al., 1999, pubmed:10417292). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (MIM:608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008; pubmed:18698615). [from MIM:209850; 2017.03.18]
Neuroligins function as ligands for the neurexins, which are cell-surface receptors. The Ca(2+)-dependent neurexin/neuroligin complex is present at synapses in the central nervous system, is required for efficient neurotransmission, and is involved in the formation of synaptic contacts (summary by Reissner et al., 2008; pubmed:18812509). [from MIM:600568; 2017.03.18]
Many to many; multiple genes in both species.
Many to many; multiple genes in both species.
Many to many; multiple genes in both species.
Many to many; multiple genes in both species. Moderate-scoring ortholog of human NLGN1 NLGN3, and NLGN4X.
Many to many; multiple genes in both species. Moderate-scoring ortholog of NLGN1, NLGN3, and NLGN4X.
Many to many; multiple genes in both species. Moderate- to high-scoring ortholog of human NLGN3, NLGN1, NLGN4X, NLGN2, and NLGN4Y.
